Synergistic activity of antibodies in the multicomponent 4CMenB vaccine

ABSTRACT

Introduction

Vaccines based on multiple antigens often induce an immune response, which is higher than that triggered by each single component, with antibodies acting cooperatively and synergistically in tackling the infection.

Areas covered

An interesting example is the antibody response induced by the 4CMenB vaccine, currently licensed for the prevention of Neisseria meningitidis serogroup B (MenB). It contains four antigenic components: Factor H binding protein (fHbp), Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and Outer Membrane Vesicles (OMV). Monoclonal and polyclonal antibodies raised by vaccination with 4CMenB show synergistic activity in complement-dependent bacterial killing. This review summarizes published and unpublished data and provides evidence of the added value of multicomponent vaccines.

Expert opinion

The ability of 4CMenB vaccine to elicit antibodies targeting multiple surface-exposed antigens is corroborated by the recent data on real-world evidences. Bactericidal activity is generally mediated by antibodies that bind to antigens highly expressed on the bacterial surface and immunologically related. However, simultaneous binding of antibodies to various surface-exposed antigens can overcome the threshold density of antigen–antibody complexes needed for complement activation. The data discussed in this review highlight the interplay between antibodies targeting major and minor antigens and their effect on functionality.

Clinical trial registration

www.clinicaltrials.gov identifiers of studies with original data mentioned in the article: NCT00937521, NCT00433914, NCT02140762, and NCT02285777.

KEYWORDS:

• 4CMenB
• antibody synergy
• bactericidal activity
• cooperative binding
• MenB vaccine
• minor OMV antigens
• Neisseria meningitidis
• NHBA
• OMV
• multicomponent vaccine
• vaccine strain coverage

Article highlights

• Multicomponent vaccines may induce antibodies acting cooperatively and synergistically in tackling the infection.

• Monoclonal and polyclonal antibodies raised by vaccination with 4CMenB show cooperative and synergistic activity in complement-mediated bacterial killing.

• Antibodies induced by fHbp, NHBA, and minor OMV components can act in concert and be functional against meningococcal strains not predicted to be covered by classical MenB prediction tools.

• The simultaneous binding of antibodies to various surface-exposed antigens can overcome the threshold density of antigen–antibody complexes needed for complement activation.

• A full understanding of the synergistic mechanisms may allow the definition of new coverage prediction tools and guide the design of multicomponent vaccines.

Trademark

Bexsero is a trademark owned by or licensed to the GSK group of companies. Trumenba is a trademark owned by Pfizer. VA-MENGOC-BC is a trademark of the Finlay Institute, Cuba. MenBvac is a trademark of the Norwegian Institute of Public Health. MeNZB is a trademark of Novartis.

Human samples

The human infant samples used in the study were obtained via a Phase II clinical trial (V72P16, NCT00937521) conducted in multiple centres after Ethical committee approval in the Czech Republic, Italy, Hungary, Chile, and Argentina between July 2009 and November 2010 in accordance with Good Clinical Practices and according to the Declaration of Helsinki. An informed consent form, which included permission for potential re-use of the biological samples, was obtained from parents or guardian of the participant in the clinical trial. Serum samples used in this analysis are pool of antiserum from 25 subjects assuring the anonymity of any subject so that no further ethical committee approval was needed. Human complement source used in the study was obtained according to Good Clinical Practice in accordance with the declaration of Helsinki. Patients have given their written consent for the use of samples of study MENB REC 2ND GEN-074 (V72_92). The study was approved by the Western Institutional Review Board (WIRB).

Declaration of interest

V Viviani was a PhD student at the University of Bologna and participated in a postgraduate studentship program at GSK at the time of the study and she is now an employee of the GSK group of companies. A Biolchi and M Pizza are employees of the GSK group of companies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors would like to thank Sarah Nosari for the contribution to the study and Giorgio Corsi for kind assistance in preparation of the artwork.

Author contributions

VV, AB, and MP have substantially contributed to the conception and design of the review article and to the interpretation of the relevant literature and they have all been involved in writing the review article.

Additional information

Funding

This work was undertaken at the request of and sponsored by GlaxoSmithKline Biologicals SA.